Abstract
Ischemic disease is among the deadliest and most disabling illnesses. Prominent examples include myocardial infarction and stroke. Most, if not all, underlying pathological changes, including oxidative stress, inflammation, and nutrient deprivation, are potent inducers of the integrated stress response (ISR). Four upstream kinases are involved in ISR signaling that sense a myriad of input stress signals and converge on the phosphorylation of serine 51 of eukaryotic translation initiation factor 2α (eIF2α). As a result, translation initiation is halted, creating a window of opportunity for the cell to repair itself and restore homeostasis. A growing number of studies show strong induction of the ISR in ischemic disease. Genetic and pharmacological evidence suggests that the ISR plays critical roles in disease initiation and progression. Here, we review the basic regulation of the ISR, particularly in response to ischemia, and summarize recent findings relevant to the actions of the ISR in ischemic disease. We then discuss therapeutic opportunities by modulating the ISR to treat ischemic heart disease, brain ischemia, ischemic liver disease, and ischemic kidney disease. Finally, we propose that the ISR represents a promising therapeutic target for alleviating symptoms of ischemic disease and improving clinical outcomes.
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Acknowledgements
We thank the members of the Wang lab for valuable discussions. This work was supported by funding from the American Heart Association (14SDG18440002, 17IRG33460191, and 19IPLOI34760325 to ZVW; 20POST35210756 to XW; 19TPA34920001 to BAR), the American Diabetes Association (1-17-IBS-120 and 7-20-IBS-218 to ZVW), the National Institute of Health (HL137723 to ZVW; HD101006, HD087351, and HL147276 to BAR), and Agencia Nacional de Investigacion y Desarrollo (ANID), Chile (FONDAP 15130011 and FONDECYT 1200490 to SL).
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GZ, SL and ZVW wrote the manuscript with the help from XW and BAR. All authors revised and approved the manuscript.
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Zhang, G., Wang, X., Rothermel, B.A. et al. The integrated stress response in ischemic diseases. Cell Death Differ 29, 750–757 (2022). https://doi.org/10.1038/s41418-021-00889-7
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DOI: https://doi.org/10.1038/s41418-021-00889-7
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